Robl in U.S. Pat. No. 5,508,272 discloses compounds of the formula ##STR4##
wherein A can be ##STR5##
X can be S, Y can be CH.sub.2, m can be one, and n can be two as possessing neutral endopeptidase and angiotensin converting enzyme inhibition activity. Among these compounds is [4S-[4.alpha.((R*), 7.alpha.10a.beta.]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl-amino]-5 -oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid which is currently undergoing clinical evaluation. This compound is reported in the literature as BMS 186,716 and as omapatrilat.
Robl discloses that the amino lactam portion of BMS 186,716, i.e. the intermediate ##STR6##
can be prepared by coupling (S)-2-amino-6,6-di-methoxyhexanoic acid, methyl ester with the N-protected amino acid ##STR7##
wherein P.sub.1 is an amino protecting group and P.sub.2 is a sulfur protecting group to give the dipeptide of the formula ##STR8##
Removal of the P.sub.2 protecting group, followed by acid catalyzed cyclization, and removal of the P.sub.1 protecting group gives [4S-(4.alpha.,7.alpha., 10a.beta.)]-octahydro-4-amino-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carb oxylic acid, methyl ester.
Robl discloses preparing (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester by converting N-protected L-.epsilon.-hydroxynorleucine to its methyl ester, oxidizing to the aldehyde of the formula ##STR9##
then reacting with trimethyl orthoformate in the presence of a strong acid catalyst, and removing the P.sub.3 protecting group.